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A Promising New Development for Treatment of Duchenne Muscular Dystrophy

A technique called exon skipping shows great potential to increase muscle strength and prolong life in people with a severe form of Duchenne muscular dystrophy (DMD). According to a study that included MDA-supported Stephen Wilton at the University of Western Australia, exon skipping improves production of a crucial muscle protein that’s missing in people with DMD. For the first time, these results were observed in mice with an especially severe form of muscular dystrophy.

The study was published in the journal Molecular Therapy on Oct. 20.

“This finding bodes well for the potential of this treatment to help humans with Duchenne, which is typically more severe than the disease seen in the standard mouse model,” said Sharon Hesterlee, senior vice president of MDA’s venture philanthropy program.

The findings, which show that exon skipping compounds can work even in mice with rapidly progressive DMD, add support to the already substantial interest shown by biotechnology and pharmaceutical companies in developing this type of compound for treatment of children and young adults with DMD. (See clinicaltrials.gov for continuously updated information on this and other drug testing.)

About exon skipping

The regions of genes that carry instructions for proteins (such as dystrophin) are known as "exons." During the processing of genetic information in cells, exons are pieced together, while other information (in the form of "introns") is removed. Then, the final instructions — "messenger RNA"— are exported out of the cell nucleus, at which time the cell can use them to make protein molecules. When a gene mutation results in missing pieces of exons, the protein that is made can be unstable or otherwise not functional.

Exon skipping changes the way messenger RNA instructions are read so that only error-free exons go into the final protein "recipe." The goal is production of a functional protein despite the presence of flawed genetic instructions.

At this time, the Dutch biotechnology company Prosensa, the UK-based pharmaceutical company GlaxoSmithKline, and the U.S. company AVI BioPharma are involved in developing exon skipping to restore dystrophin protein production in DMD.

Two exon skipping compounds, one developed by Prosensa and the other by AVI BioPharma, have already shown safety in boys with DMD and are now undergoing further clinical testing.

MDA funded much of the initial basic science underlying the development of this strategy and continues to support Wilton and others to optimize it.

About DMD

DMD is a degenerative muscle disease caused by any of a number of mutations in the X-chromosome gene that carries instructions for the muscle protein known as dystrophin.

Without dystrophin, muscle fibers are abnormally fragile and break down under the stress of contractions. The muscle degeneration affects all the skeletal muscles, including those controlling breathing, and the heart. Significant disability by the teen years is almost universal, as is death by early adulthood from respiratory or cardiac failure.

Like other X-chromosome-linked diseases, DMD affects males almost exclusively, although females can sometimes develop symptoms.

About these findings

The unique aspect of today's findings compared to previous studies of exon skipping in mice is that the mice these researchers treated were missing not only dystrophin but another protein known as utrophin, making their disease much more severe and closer to human DMD than the dystrophin-deficient mice previously tested. (Humans with DMD lack only dystrophin, but for unknown reasons, their disease is more severe than that of mice that lack only dystrophin.)

Here, we report a remarkable prevention of the dystrophic pathology and improvement of the muscle function of the severely affected [dystrophin- and utrophin-deficient] mice," according to study authors. They say the type of exon skipping compound they used, known as a PPMO, shows "therapeutic, drug-like effects not only in relatively benign [dystrophin-deficient mice] but also in very severe [dystrophin- and utrophin-deficient mice], suggesting great potential for these compounds in the systemic treatment of DMD."

The researchers note that, for technical reasons, they had to give the PPMO exon skipping compound by injecting it into the abdomen in the mice, but that they suspect intravenous delivery might be even more effective.

About MDA

MDA is the nonprofit health agency dedicated to curing muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides comprehensive health care and support services, advocacy and education.